During the last grant period we investigated several antigen (Ag) targeting strategies, where Ags are efficiently delivered into the immune system by coupling to antibodies (Abs) that bind receptors on Ag presenting cells (APCs). Depending on what APCs are targeted, different kinds of immune responses are induced. Ag is usually coupled to an Ab specific for a receptor expressed on dendritic cells (DCs), and then the Ag-anti- receptor is inoculated with an adjuvant. We found that when Ag is targeted to both B cells and DCs by coupling it to a monoclonal Ab (mAb) specific for the CD180 receptor, which is related to members of the Toll-like receptor (TLR) family, strong Ab and T cell responses are induced. Ag coupled to anti-CD180 mAb, when injected into wildtype (WT) mice rapidly induced high levels of Ag-specific IgG responses, and higher and more sustained than those induced by Ag in alum. Ag conjugated to CD180 (Ag-?CD180) rapidly induces IgG Ab responses not only in WT mice but also in mice immunodeficient in T cell, B cell and type I interferon (IFN) innate immune responses. These findings suggest that targeting Ag to CD180 may be a safe and effective means for vaccinating even the immune-compromised. A major Aim of this proposal is to define how CD180- based Ag targeting programs rapid B cell and T cells responses. A second Aim will be to define how best to induced long-lasting protective immune responses using a CD180- based vaccine and a mouse model for lethal West Nile virus (WNV) infection. Ag- ?CD180 immunization induces IgG Ab responses in a number of immunodeficient mice and can induce protective immunity to WNV even in BAFFR-deficient mice that are deficient in mature B cells. Thus, a third Aim will be to define a CD180-based vaccine that can induce strong protective immunity in immunocompromised mice including B cell or T cell help deficient mice and aged mice. A major goal will be to define a one shot vaccine that can induce protective immunity in an immunodeficient mouse model. These studies could lead to identification of a novel and safe vaccine platform useful for immunizing immunodeficient, neonatal or elderly individuals and potentially for use as a therapeutic vaccine.